The mammalian brain maintains the capacity to generate new neurons for tissue homeostasis and after injuries, which is driven by neural stem/progenitor cells (NSCs). The long term goal of the proposed studies is to understand the molecular and cellular mechanisms of autophagy pathway and genes in the regulation of NSCs. Autophagy is a highly conserved cellular process for maintenance of cellular homeostasis, and dysfunctions in autophagy have been implicated in many disorders, including neurodegenerative diseases. Despite increasing research on autophagy in recent years, little is known about the role and mechanisms of autophagy in the regulation of tissue stem cells such as NSCs. FIP200 (FAK-family Interacting Protein of 200 kDa) was initially identified in our laboratory and later shown as one component of the ULK1/Atg13/FIP200 complex essential for autophagy induction. Very recently, we showed that conditional knockout (cKO) of FIP200 resulted in the depletion of NSCs and their aberrant differentiation, providing the first evidence for a role of autophagy in postnatal NSCs. In prelim studies, we found that autophagy inhibition by deletion of Atg5 or Atg16L1 (autophagy genes required for autophagosome maturation) did not affect NSCs, and further comparative analyses of FIP200, Atg5 and Atg16L1 cKO mice suggested that FIP200, but not Atg5 and Atg16L1, deletion caused p62 aggregation in NSCs. Generation and analysis of a FIP200 and p62 double cKO mice suggested that the preferential p62 aggregates formation plays a crucial role in triggering aberrant superoxide increase leading to defective NSCs primarily by impairing SOD functions. In addition, we showed that knockdown of Atg13 (FIP200 partner in the autophagy induction complex) inhibited NSC self-renewal in vitro, and identified residues 582-585 in FIP200 required for its binding to Atg13. We then created a novel FIP200 knock-in mutant mice containing FIP200x allele lacking binding to Atg13 and showed that KI/KI MEFs were defective in both basal and starvation-induced autophagy. Lastly, microarray analysis of neurospheres from various mice revealed elevated expression of multiple genes associated with inflammation upon FIP200 deletion, which were not rescued by p53 inactivation. Moreover, an increased infiltration of microglia was found in the SVZ of FIP200 cKO mice, as well as FIP200 and p53 double cKO mice, suggesting an interesting possibility that the infiltrating microglias may be responsible for the p53-independent, aberrant differentiation of NSCs upon deletion of FIP200. Based on these preliminary and previous studies, we propose to 1). investigate the mechanisms of p62 aggregates in mediating NSC regulation by autophagy, 2). analyze FIP200-mediated autophagy function in the regulation of NSCs, and 3). explore the role and mechanisms of elevated microglia infiltration in the aberrant differentiation of NSCs upon FIP200 ablation. Together, these studies will significantly advance our understanding of the mechanisms of NSC regulation by autophagy that may contribute to future design of more effective therapies for neurodegenerative and other related diseases.